Search

CN-117120422-B - Substituted naphthyl P38 alpha mitogen-activated protein kinase inhibitors

CN117120422BCN 117120422 BCN117120422 BCN 117120422BCN-117120422-B

Abstract

The invention discloses a substituted naphthyl p38 alpha mitogen-activated protein kinase inhibitor, a pharmaceutical composition thereof, and the use of the substituted naphthyl p38 alpha mitogen-activated protein kinase inhibitor and the pharmaceutical composition thereof for treating diseases.

Inventors

  • Adam Galan
  • Wendy Rowe
  • RITU LAL

Assignees

  • GEN1E生命科学公司

Dates

Publication Date
20260512
Application Date
20220321
Priority Date
20210323

Claims (8)

  1. 1. A compound having the structure of formula (6): (6) Or a pharmaceutically acceptable salt thereof, wherein, R 1 is C 1-4 alkanediyl; R 2 is 3-substituted morpholin-4-yl; R 3 is-S (=o) 2 -; R 4 is-N (R 5 ) 2 , wherein each R 5 is independently selected from hydrogen and C 1-4 alkyl; R 4 is bonded to the 5-position of the naphthyl moiety, and The substituent is =o.
  2. 2. The compound according to claim 1, wherein, R 1 is methane diyl.
  3. 3. The compound of claim 1, wherein the compound is selected from the group consisting of: 5-amino-N- (4- ((3-oxo-morpholino) methyl) phenyl) naphthalene-1-sulfonamide; 5- (methylamino) -N- (4- ((3-oxomorpholino) methyl) phenyl) naphthalene-1-sulfonamide, and 5- (Dimethylamino) -N- (4- ((3-oxomorpholino) methyl) phenyl) naphthalene-1-sulfonamide; Or a pharmaceutically acceptable salt of any of the above.
  4. 4. The compound of claim 1, wherein the compound is 5-amino-N- (4- ((3-oxomorpholino) methyl) phenyl) naphthalene-1-sulfonamide (5) or a pharmaceutically acceptable salt thereof: 。
  5. 5. the compound of claim 1, wherein the compound is 5- (methylamino) -N- (4- ((3-oxomorpholino) methyl) phenyl) naphthalene-1-sulfonamide (2) or a pharmaceutically acceptable salt thereof: 。
  6. 6. the compound of claim 1, wherein the compound is 5- (dimethylamino) -N- (4- ((3-oxomorpholino) methyl) phenyl) naphthalene-1-sulfonamide (3) or a pharmaceutically acceptable salt thereof: 。
  7. 7. a pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle.
  8. 8. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, in the manufacture of a medicament for treating a viral disease in a patient, wherein the viral disease is SARS-CoV-2.

Description

Substituted naphthyl P38 alpha mitogen-activated protein kinase inhibitors The present application is in accordance with the rights of U.S. c. ≡119 (e) as filed on day 23 at 3 at 2021, U.S. provisional application No. 63/164,664, which is incorporated herein by reference in its entirety. Technical Field The present disclosure relates to substituted naphthyl p38α mitogen-activated protein kinase inhibitors, pharmaceutical compositions thereof, and the use of substituted naphthyl p38α mitogen-activated protein kinase inhibitors and pharmaceutical compositions thereof for the treatment of diseases. Sequence listing The present application contains a sequence listing that has been electronically submitted in ASCII format and is incorporated herein by reference in its entirety. An ASCII copy created at 2022, 3, 21 was named 67LZ-000610 PC-34966_SL.txt and was 755 bytes in size. Background Mitogen-activated protein kinases (MAPKs) are serine/threonine protein kinases that process and regulate cellular properties in response to a broad range of extracellular stimuli. These enzymes phosphorylate serine or threonine OH groups in proteins and play an important role in the regulation of cell proliferation, differentiation, survival and apoptosis. In mammalian cells, several different MAPKs have been identified, including p38 MAPK. P38 MAPK is a class of MAPK that responds to stress stimuli such as inflammatory cytokines and Reactive Oxygen Species (ROS), and is involved in a wide range of signaling pathways that stimulate diverse biological functions. For example, p38 MAPK has been found to play an important role in the regulation of the pro-inflammatory signaling network and in the biosynthesis of cytokines, including tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) in immune cells. Studies have shown that p38 MAPK contributes to the pathogenesis of chronic inflammation, leading to preclinical or clinical trials for the use of p38 MAPK inhibitors in inflammatory diseases such as rheumatoid arthritis and asthma. P38 MAPK comprises four subtypes (α, β, γ, and δ). p38α MAPK was the first identified p38 MAPK isoform and was first thought to be a stress-induced kinase that can be activated by Lipopolysaccharide (LPS) and inflammatory cytokines. Inhibition of p38 MAPK has been shown to be effective in alleviating the symptoms of inflammatory diseases such as rheumatoid arthritis, cardiovascular disease and inflammatory pain. Many p38 MAPK catalytic inhibitors are poorly effective and cause toxicity, possibly due to loss of activity on non-inflammatory p38 and p38 a-dependent deregulation responses. It is desirable to have p38α MAPK inhibitors for the treatment of inflammatory and neoplastic diseases that can selectively block certain p38α MAPK functions and maintain critical deregulated and homeostatic functions. Disclosure of Invention According to the invention, the compound has the structure of formula (6): (6) Or a pharmaceutically acceptable salt thereof, wherein, R 1 is selected from the group consisting of C 1-4 alkanediyl, C 1-4 heteroalkanediyl, substituted C 1-4 alkanediyl, and substituted C 1-4 heteroalkanediyl; R 2 is substituted C 5-8 heterocycloalkyl; R 3 is selected from the group consisting of-C (=O) -and-S (=O) 2 -, and R 4 is selected from-N (R 5)2, wherein each R 5 is independently selected from hydrogen and C 1-4 alkyl. According to the invention, the pharmaceutical composition comprises a compound according to the invention or a pharmaceutically acceptable salt thereof. According to the invention, a method of treating a disease in a patient comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound according to the invention, or a pharmaceutically acceptable salt thereof, wherein the disease is treated by inhibiting the p38α MAPK receptor. Drawings The drawings described herein are for illustration purposes only. The drawings are not intended to limit the scope of the present disclosure. FIG. 1 shows the cell viability (black) and IC 50 (red) curves of SARS-CoV-2 cell line treated with compound (4). FIG. 2 shows the cell viability (black) and IC 50 (red) curves of SARS-CoV-2 cell line treated with compound (1). FIG. 3 shows the cell viability (black) and IC 50 (red) curves of SARS-CoV-2 cell line treated with compound (2). Detailed Description No dash ("-") between two letters or symbols is used to indicate a point of attachment for a moiety or substituent. For example, -CONH 2 is attached through a carbon atom. "Alkyl" refers to a saturated, branched or straight-chain monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Examples of alkyl groups include methyl, ethyl, such as ethyl, vinyl, ethynyl, propyl, such as prop-1-yl, prop-2-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-1-yn-1-yl, prop-2-yn-1-yl, and the like, buty